(306) Assessing Causality in HIV-Positive Patients with Antituberculosis And/or Antiretroviral Therapy – Associated Liver Injury

Saturday, August 27, 2022

8:00 AM – 6:00 PM CEST

Location: Hall C

Publication Number: 980

Presenting Author(s)

Hannah May Gunter, MBCHB
– Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, City of Cape Town, Western Cape, South Africa

Co-Author(s)

Karen Cohen
– Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa, Western Cape, South Africa
Gayle Tatz
– Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa, Cape Town, Western Cape, South Africa
Gary Maartens
– Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa, Western Cape, South Africa
Wendy Spearman
– Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa, Western Cape, South Africa
Ushma Mehta
– Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa, Western Cape, South Africa

Background: Drug-induced liver injury (DILI) is one of the most common adverse drug reactions resulting in hospital admission and death in South Africa. Antituberculosis therapy (ATT) and antiretroviral therapy (ART) are frequently implicated. Patients taking ATT and/or ART are often taking multiple concomitant drugs known to cause liver injury, which poses challenges for causality assessment. There is a need for a sensitive and specific causality assessment method to determine whether a suspected liver injury is a DILI, and which drug was the most likely cause.

Objectives: To compare performance of the Roussel Uclaf Causality Assessment Method (RUCAM) with causality assessment by multidisciplinary expert panel review in identifying a DILI due to ATT and/or ART

Methods: Cases were drawn from a prospective registry of hospitalised adults (≥18 years of age) with liver injury suspected to be due to ATT and/or ART, in Cape Town, South Africa. Participants included in this study had to fulfil American Thoracic Society criteria for ATT interruption (alanine transaminase [ALT]≥5 times upper limit of normal [ULN]/ALT≥3 times [ULN] and symptomatic). Causality assessment by a multidisciplinary expert panel review served as the reference standard for the analysis. The panel ranked potentially implicated drugs as certain, probable, possible, or unlikely causes, guided by the World Health Organization Uppsala Monitoring Centre causality assessment criteria. The RUCAM was performed for each potentially implicated drug. We calculated sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause for liver injury.

Results: We included 48 participants. All were HIV positive. Thirty-seven were taking ATT and 38 ART, with 27 taking concomitant ATT and ART. There was a median of 6 potentially hepatotoxic drugs per case (range 4 to 7). Sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause of liver injury compared with expert panel review was 11% (95% confidence interval [CI] 2%-28%) and 85% (95% CI 62%-97%) respectively. Implicated drugs (times ranked probable/certain by panel) were isoniazid (18/0), pyrazinamide (17/0), rifampicin (15/1), efavirenz (6/4), lopinavir/ritonavir (1/0).

Conclusions: HIV-positive patients with liver injury in this case-series were receiving multiple potentially implicated drugs, which may increase the risk of liver injury and complicates causality assessment. Compared with expert panel review, the RUCAM had low sensitivity in detecting drugs that were probable or certain causes of liver injury.